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C-Kit in Atherosclerosis

C-Kit 在动脉粥样硬化中的应用

基本信息

批准号：
9319457
负责人：
Roberto Irenardo Vazquez Padron
金额：
$ 8.21万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319457
关键词：
American Aorta Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Behavior Blood Vessels C-KIT Gene Carotid Arteries Cause of Death Cell Culture Techniques Cells Cholesterol Chronic Disease Clinical Complex Coronary Arteriosclerosis Development Disease Disease Progression Encapsulated Endothelium Enterobacteria phage P1 Cre recombinase Equilibrium Genes Genetic Transcription Genetically Engineered Mouse Goals High Fat Diet Impairment Inflammation Inflammatory Invaded Knockout Mice Knowledge Lesion Life Style Link Lipids MAP Kinase Gene Mediating Molecular Mus Muscle Cells Mutant Strains Mice Nuclear Outcome Study Pathologic Peripheral arterial disease Pharmaceutical Preparations Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Protein Dephosphorylation Proto-Oncogene Protein c-kit Risk Role Rupture Serum Response Factor Signal Transduction Smooth Muscle Smooth Muscle Myocytes Specificity Stem Cell Factor Symptoms Tamoxifen Testing Translating Tyrosine United States Vascular Smooth Muscle cadherin 5 cerebrovascular design disability feeding gain of function human disease hypercholesterolemia in vivo inhibitor/antagonist loss of function mouse model myocardin new therapeutic target novel novel therapeutic intervention prevent public health relevance receptor reconstitution transcription factor vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the leading cause of death and illness in the United States despite all advances in lipid- lowering drugs and lifestyle changes designed to reduce cholesterol levels. Atherosclerosis is a chronic disease that causes accumulation of plaques in the arterial walls. Smooth muscle cells (SMCs) that migrate from the media after phenotypic switching significantly contribute to atherosclerosis and plaque stability. However, the molecular mechanisms responsible for SMC phenotypic modulation in disease development still remain unclear. Consequently, we hypothesize that c-Kit signaling stabilizes the SMC contractile phenotype in arterial walls, which controls the progression of the disease in early atherosclerosis and decreases the risk of plaque rupture in advanced lesions. We support the hypothesis with preliminary studies that demonstrate: 1) the expression of c-Kit in healthy and diseased human and mouse aortas, 2) the role of c-Kit in SMC phenotypic switching, 3) increased systemic atherosclerosis in hyperlipidemic mice with impaired SCF or c-Kit functions, and 4) increased risk for vulnerable plaque rupture in c-Kit deficient mice . We will prove our hypothesis in three specific aims. In aim 1 we propose to test whether c-Kit loss or gain-of-function in SMCs alters atherosclerosis development in hyperlipidemic mice. We will make use of a novel genetically engineered mouse and a newly designed inducible lentivector to inactivate or activate the c-Kit gene in arterial SMCs. In aim 2 we will examine the molecular mechanisms by which c-Kit maintains the contractile phenotype in SMCs. We will use culture cells from c-Kit conditional knockout mice to demonstrate the relevance of the c- Kit/PI3K/Akt signaling axis and DUSP mediated dephosphorylation of MAPK in maintaining the transcription of SMC contractile genes. Finally, in aim 3 we will investigate the impact of altering vascular c-Kit signaling in vascular inflammation and atherosclerotic plaque rupture in vivo. We will evaluate spontaneous plaque rupture in HFD fed conditional mice after tamoxifen feeding to inactivate the c-Kit gene in the plaque. Together, these studies will advance our knowledge about the role of c-Kit in atherosclerosis and will furnish new therapeutic targets to prevent and eventually mitigate the devastating effects of atherosclerosis.